EP0796271B1 - Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten - Google Patents
Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten Download PDFInfo
- Publication number
- EP0796271B1 EP0796271B1 EP95941015A EP95941015A EP0796271B1 EP 0796271 B1 EP0796271 B1 EP 0796271B1 EP 95941015 A EP95941015 A EP 95941015A EP 95941015 A EP95941015 A EP 95941015A EP 0796271 B1 EP0796271 B1 EP 0796271B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- formula
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- CHOGNBXWAZDZBM-UHFFFAOYSA-N 4-(aminomethyl)benzenecarboximidamide Chemical class NCC1=CC=C(C(N)=N)C=C1 CHOGNBXWAZDZBM-UHFFFAOYSA-N 0.000 title description 3
- 108010016626 Dipeptides Proteins 0.000 title description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 3
- -1 C1-C3-fluoroalkyl Chemical group 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 8
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000005840 aryl radicals Chemical class 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 206010038563 Reocclusion Diseases 0.000 claims description 2
- 230000009089 cytolysis Effects 0.000 claims description 2
- 238000010297 mechanical methods and process Methods 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 230000009424 thromboembolic effect Effects 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 28
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 0 C*C(*)(*)NC Chemical compound C*C(*)(*)NC 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 9
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 150000001409 amidines Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- OISYEZCXYOOZOU-FDOHDBATSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(4-cyanophenyl)methyl]pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C#N)C1=CC=CC=C1 OISYEZCXYOOZOU-FDOHDBATSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- KNWCDYSKJSREAQ-VKHMYHEASA-N (2s)-1,3-oxazolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1NCCO1 KNWCDYSKJSREAQ-VKHMYHEASA-N 0.000 description 3
- FYCRNRZIEVLZDO-BYPYZUCNSA-N (2s)-morpholin-4-ium-2-carboxylate Chemical compound OC(=O)[C@@H]1CNCCO1 FYCRNRZIEVLZDO-BYPYZUCNSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 3
- 239000003868 thrombin inhibitor Substances 0.000 description 3
- 229950001139 timonacic Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- SAUDSWFPPKSVMK-LBPRGKRZSA-N (2s)-2-(n-phenylanilino)propanoic acid Chemical compound C=1C=CC=CC=1N([C@@H](C)C(O)=O)C1=CC=CC=C1 SAUDSWFPPKSVMK-LBPRGKRZSA-N 0.000 description 2
- CSKSDAVTCKIENY-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CCCN1 CSKSDAVTCKIENY-WCCKRBBISA-N 0.000 description 2
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- QREZLLYPLRPULF-UHFFFAOYSA-N 4-(aminomethyl)benzonitrile;hydron;chloride Chemical compound Cl.NCC1=CC=C(C#N)C=C1 QREZLLYPLRPULF-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IADUEWIQBXOCDZ-VKHMYHEASA-N Azetidine-2-carboxylic acid Natural products OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 2
- SCOHOFSBWBAXLU-FTBISJDPSA-N CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)CNS(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1 Chemical compound CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)CNS(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1 SCOHOFSBWBAXLU-FTBISJDPSA-N 0.000 description 2
- BFVWIFBFSIWKIY-XZVFQGBBSA-N CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@@H](CC=2C=CC=CC=2)NS(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1 Chemical compound CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@@H](CC=2C=CC=CC=2)NS(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1 BFVWIFBFSIWKIY-XZVFQGBBSA-N 0.000 description 2
- QIONPIFGYVOSFJ-UHFFFAOYSA-N CC(O)=O.NCC(C=C1)=CC=C1C(N)=N Chemical compound CC(O)=O.NCC(C=C1)=CC=C1C(N)=N QIONPIFGYVOSFJ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000003482 Pinner synthesis reaction Methods 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- BCROMQFHHKBCQZ-MOPGFXCFSA-N [(2r)-1-[(2s)-2-[(4-carbamimidoylphenyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]sulfamic acid Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@@H](CC=2C=CC=CC=2)NS(O)(=O)=O)CCC1 BCROMQFHHKBCQZ-MOPGFXCFSA-N 0.000 description 2
- USRDGCPKYYJOAI-NSLUPJTDSA-N acetic acid (2S)-N-[(4-carbamimidoylphenyl)methyl]-1-[(2R)-3-phenyl-2-(propan-2-ylsulfamoylamino)propanoyl]pyrrolidine-2-carboxamide Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)NC(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 USRDGCPKYYJOAI-NSLUPJTDSA-N 0.000 description 2
- YUQFHUITFQZABL-NSLUPJTDSA-N acetic acid;(2s)-n-[(4-carbamimidoylphenyl)methyl]-1-[(2r)-3-phenyl-2-(propan-2-ylsulfonylamino)propanoyl]pyrrolidine-2-carboxamide Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)C(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 YUQFHUITFQZABL-NSLUPJTDSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 2
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000565 sulfonamide group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- OLFQKLXNHSHUSX-YADHBBJMSA-N (2S)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-1-[(2R)-3-phenyl-2-(propan-2-ylsulfamoylamino)propanoyl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](NS(=O)(=O)NC(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(=N)NO)C1=CC=CC=C1 OLFQKLXNHSHUSX-YADHBBJMSA-N 0.000 description 1
- PICQEJDBZKDWOD-CQSZACIVSA-N (2r)-2-(benzenesulfonamido)-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)C1=CC=CC=C1 PICQEJDBZKDWOD-CQSZACIVSA-N 0.000 description 1
- RRSYAACXBJFWRS-GOSISDBHSA-N (2r)-2-(naphthalen-2-ylsulfonylamino)-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NS(=O)(=O)C=1C=C2C=CC=CC2=CC=1)C1=CC=CC=C1 RRSYAACXBJFWRS-GOSISDBHSA-N 0.000 description 1
- ZPRHVPHDENDZTP-CABCVRRESA-N (2s)-1-[(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@@H](NC(=O)OC(C)(C)C)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZPRHVPHDENDZTP-CABCVRRESA-N 0.000 description 1
- ZEVSMNYREQIAQK-QNCHGCKQSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(4-carbamimidoylphenyl)methyl]pyrrolidine-2-carboxamide;dihydrochloride Chemical compound Cl.Cl.C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 ZEVSMNYREQIAQK-QNCHGCKQSA-N 0.000 description 1
- QTRUYPSURQNTKH-CABCVRRESA-N (2s)-1-[(2r)-3-phenyl-2-(propan-2-ylsulfonylamino)propanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@@H](NS(=O)(=O)C(C)C)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 QTRUYPSURQNTKH-CABCVRRESA-N 0.000 description 1
- WULMVFAMVNZBIO-HNNXBMFYSA-N (2s)-1-[2-(naphthalen-2-ylsulfonylamino)acetyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CNS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 WULMVFAMVNZBIO-HNNXBMFYSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- DTGOUWNVHDROOR-LBPRGKRZSA-N (2s)-2-(dicyclohexylamino)propanoic acid Chemical compound C1CCCCC1N([C@@H](C)C(O)=O)C1CCCCC1 DTGOUWNVHDROOR-LBPRGKRZSA-N 0.000 description 1
- VNLFZVJYRYRAIX-YFKPBYRVSA-N (2s)-2-(tert-butylamino)-3-hydroxypropanoic acid Chemical compound CC(C)(C)N[C@@H](CO)C(O)=O VNLFZVJYRYRAIX-YFKPBYRVSA-N 0.000 description 1
- PECGVEGMRUZOML-AWEZNQCLSA-N (2s)-2-amino-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C([C@H](N)C(O)=O)C1=CC=CC=C1 PECGVEGMRUZOML-AWEZNQCLSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- LJDPNQPYLMLMRY-NRFANRHFSA-N (2s)-n-[(4-carbamimidoylphenyl)methyl]-1-[2-(naphthalen-1-ylsulfonylamino)acetyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)CNS(=O)(=O)C=2C3=CC=CC=C3C=CC=2)CCC1 LJDPNQPYLMLMRY-NRFANRHFSA-N 0.000 description 1
- BMVOPRNONPLARR-IHLOFXLRSA-N (2s)-n-[(4-cyanophenyl)methyl]-1-[(2r)-2-(naphthalen-2-ylsulfonylamino)-3-phenylpropanoyl]pyrrolidine-2-carboxamide Chemical compound O=C([C@H]1N(CCC1)C(=O)[C@@H](CC=1C=CC=CC=1)NS(=O)(=O)C=1C=C2C=CC=CC2=CC=1)NCC1=CC=C(C#N)C=C1 BMVOPRNONPLARR-IHLOFXLRSA-N 0.000 description 1
- LPHCTVUEYNELEM-PKTZIBPZSA-N (2s)-n-[(4-cyanophenyl)methyl]-1-[(2r)-3-phenyl-2-(propan-2-ylsulfamoylamino)propanoyl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](NS(=O)(=O)NC(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C#N)C1=CC=CC=C1 LPHCTVUEYNELEM-PKTZIBPZSA-N 0.000 description 1
- CTTAZLWDEWHLTA-PKTZIBPZSA-N (2s)-n-[(4-cyanophenyl)methyl]-1-[(2r)-3-phenyl-2-(propan-2-ylsulfonylamino)propanoyl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](NS(=O)(=O)C(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C#N)C1=CC=CC=C1 CTTAZLWDEWHLTA-PKTZIBPZSA-N 0.000 description 1
- TXOJELPEDAZTCY-QHCPKHFHSA-N (2s)-n-[(4-cyanophenyl)methyl]-1-[2-(naphthalen-2-ylsulfonylamino)acetyl]pyrrolidine-2-carboxamide Chemical class O=C([C@@H]1CCCN1C(CNS(=O)(=O)C=1C=C2C=CC=CC2=CC=1)=O)NCC1=CC=C(C#N)C=C1 TXOJELPEDAZTCY-QHCPKHFHSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- LDPCMSFHHDVNDF-UHFFFAOYSA-N 2-(azetidin-2-yl)acetic acid Chemical group OC(=O)CC1CCN1 LDPCMSFHHDVNDF-UHFFFAOYSA-N 0.000 description 1
- CTVIWLLGUFGSLY-UHFFFAOYSA-N 2-(cyclohexylazaniumyl)-2-methylpropanoate Chemical compound OC(=O)C(C)(C)NC1CCCCC1 CTVIWLLGUFGSLY-UHFFFAOYSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-UHFFFAOYSA-N 2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)C(C)NC1CCCCC1 BVAUMRCGVHUWOZ-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- HTCSFFGLRQDZDE-UHFFFAOYSA-N 2-azaniumyl-2-phenylpropanoate Chemical compound OC(=O)C(N)(C)C1=CC=CC=C1 HTCSFFGLRQDZDE-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LFIWXXXFJFOECP-UHFFFAOYSA-N 4-(aminomethyl)benzonitrile Chemical compound NCC1=CC=C(C#N)C=C1 LFIWXXXFJFOECP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- FABSNCJOVBGLJM-YYMXPCSWSA-N C(#N)C1=CC=C(CNC([C@H]2N(CCC2)C([C@H](NC(=O)OC(C)(C)C)CC2=CC=CC=C2)=O)=O)C=C1.C(N)(=N)C1=CC=C(CNC([C@H]2N(CCC2)C([C@H](NC(=O)OC(C)(C)C)CC2=CC=CC=C2)=O)=O)C=C1 Chemical compound C(#N)C1=CC=C(CNC([C@H]2N(CCC2)C([C@H](NC(=O)OC(C)(C)C)CC2=CC=CC=C2)=O)=O)C=C1.C(N)(=N)C1=CC=C(CNC([C@H]2N(CCC2)C([C@H](NC(=O)OC(C)(C)C)CC2=CC=CC=C2)=O)=O)C=C1 FABSNCJOVBGLJM-YYMXPCSWSA-N 0.000 description 1
- SEKDCHANUTYCOB-OUPRKWGVSA-N CC(O)=O.C([C@@H](NS(=O)(=O)CCCCCCCC)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)CCCCCCCC)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 SEKDCHANUTYCOB-OUPRKWGVSA-N 0.000 description 1
- XBKWBMPHCVZUIC-CEGNZRHUSA-N CC(O)=O.C([C@@H](NS(=O)(=O)CCCCCCCCCCCCCCCC)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)CCCCCCCCCCCCCCCC)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 XBKWBMPHCVZUIC-CEGNZRHUSA-N 0.000 description 1
- RXHUZHSOKMZAFT-BHDTVMLSSA-N CC(O)=O.C([C@@H](NS(=O)(=O)N(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)N(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 RXHUZHSOKMZAFT-BHDTVMLSSA-N 0.000 description 1
- ROGPAPKWNVQIDO-VOMIJIAVSA-N CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@@H](CC=2C=CC=CC=2)NS(=O)(=O)C(F)(F)F)CCC1 Chemical compound CC(O)=O.C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@@H](CC=2C=CC=CC=2)NS(=O)(=O)C(F)(F)F)CCC1 ROGPAPKWNVQIDO-VOMIJIAVSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- HIOXVGFOSYDIRC-UXHICEINSA-N [(2r)-1-[(2s)-2-[(4-cyanophenyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]sulfamic acid Chemical compound C([C@@H](NS(=O)(=O)O)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C#N)C1=CC=CC=C1 HIOXVGFOSYDIRC-UXHICEINSA-N 0.000 description 1
- IHAQIYVLLUNTGZ-RFPXDPOKSA-N acetic acid (2S)-1-[(2R)-2-(butylsulfonylamino)-3-phenylpropanoyl]-N-[(4-carbamimidoylphenyl)methyl]pyrrolidine-2-carboxamide Chemical compound CC(O)=O.C([C@@H](NS(=O)(=O)CCCC)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C(N)=N)C1=CC=CC=C1 IHAQIYVLLUNTGZ-RFPXDPOKSA-N 0.000 description 1
- OMCWXFSQPKBREP-UHFFFAOYSA-N acetic acid;hydroiodide Chemical compound I.CC(O)=O OMCWXFSQPKBREP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- HYOWVAAEQCNGLE-JTQLQIEISA-N alpha-methyl-L-phenylalanine Chemical compound OC(=O)[C@](N)(C)CC1=CC=CC=C1 HYOWVAAEQCNGLE-JTQLQIEISA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- AGRDPCWQGGNEQL-UHFFFAOYSA-N n-propan-2-ylsulfamoyl chloride Chemical compound CC(C)NS(Cl)(=O)=O AGRDPCWQGGNEQL-UHFFFAOYSA-N 0.000 description 1
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 description 1
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ORGUZAVAGHRLHN-HNNXBMFYSA-N tert-butyl (2s)-2-[(4-cyanophenyl)methylcarbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC1=CC=C(C#N)C=C1 ORGUZAVAGHRLHN-HNNXBMFYSA-N 0.000 description 1
- UGQGMWVWVNHXKW-PKTZIBPZSA-N tert-butyl n-[(2r)-1-[(2s)-2-[(4-cyanophenyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound C([C@@H](NC(=O)OC(C)(C)C)C(=O)N1[C@@H](CCC1)C(=O)NCC=1C=CC(=CC=1)C#N)C1=CC=CC=C1 UGQGMWVWVNHXKW-PKTZIBPZSA-N 0.000 description 1
- RITFNTOBNVNPGP-INIZCTEOSA-N tert-butyl n-[2-[(2s)-2-[(4-cyanophenyl)methylcarbamoyl]pyrrolidin-1-yl]-2-oxoethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC1=CC=C(C#N)C=C1 RITFNTOBNVNPGP-INIZCTEOSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to dipeptidic p-amidinobenzylamides with N-terminal sulfonyl or aminosulfonyl residues, their Production and their use as thrombin inhibitors.
- WO 93/11152 describes linear amidino-containing thrombin inhibitors, which can also contain a sulfonamide group.
- EP 601 459 describes linear and heterocyclic thrombin inhibitors, which have a sulfonamide group.
- aryl denotes mono- or bicyclic aromatic Groups which contain 6 to 10 carbon atoms in the ring system, e.g. Phenyl or naphthyl, and with up to three identical or different Substituents can be provided.
- heteroaryl refers to 5- or 6-membered aromatic rings containing 1 or 2 heteroatoms such as N, O or S. can and to which an aryl ring can be fused.
- residues R 1 , A and B are linked to one another as shown in structure I, the amino acid residues in A preferably (D) -configured and the amino acid residues in B preferably (L) -configured.
- the compounds of formula I as such or in the form of their salts with physiologically acceptable acids are: hydrochloric acid, citric acid, tartaric acid, Lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, Formic acid, maleic acid, fumaric acid, maleic acid, succinic acid, Hydroxy succinic acid, sulfuric acid, glutaric acid, Aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, Oxalic acid, ascorbic acid and acetylglycine.
- the invention further relates to the intermediates of the formula IV wherein R 1 , A and B have the meaning given and which can be used to prepare the compounds I.
- the compounds I can be prepared starting from the ⁇ -amino acid HA-OH or from the N-protected cyclic amino acid B-OH according to reaction scheme I or II.
- R 7 H or C 1 -C 4 alkyl
- R 8 C 1 -C 4 alkyl, preferably methyl or t-butyl
- R 9 CN or and P is a protecting group, preferably t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
- the protected amino acids PA-OH and HB-OR 8 can be coupled to the dipeptide PAB-OR 8 and then reacted after splitting off P with R 1 SO 2 Cl or from R 8 with p-cyano- or p-amidinobenzylamine, the reaction sequence can be any.
- R 1 -SO 2 -A-OH can also be coupled directly with para-HB-NHCH 2 C 6 H 4 R 9 to the end product I or intermediate IV.
- Boc protective groups are removed hydrogenolytically with HCl / dioxane or CF 3 COOH / methylene chloride, Cbz protective groups or with HF.
- the saponification of ester functions is carried out with NaOH or LiOH in an alcoholic solvent such as methanol or ethanol.
- t-Butyl esters are saponified with acids, for example CF 3 COOH.
- reaction with the sulfonyl chlorides R 1 -SO 2 Cl in the presence of an organic base such as triethylamine, pyridine or N, N-diisopropylethylamine is carried out in organic solvents such as CH 2 Cl 2 , THF or DMF.
- organic solvents such as CH 2 Cl 2 , THF or DMF.
- the reaction is carried out in the presence of aqueous alkali metal hydroxide or carbonate solutions.
- amidines are prepared from the nitrile precursors by the classic Pinner synthesis (R. Roger and DG Neilson, Chem. Rev. 1961, 61 , 179) or preferably by a modified Pinner synthesis which proceeds as an intermediate via iminothioester salts (H. Vieweg et al., Pharmacy 1984, 39 , 226).
- the catalytic hydrogenation of N-hydroxyamidines, which are accessible by adding hydroxylamine to the cyano group, with Raney Ni or Pd / C in alcoholic solvents also leads to amidines (BJ Broughton et al., J. Med. Chem. 1975, 18 , 1117 ).
- the new compounds can be used for therapy and prophylaxis of all diseases in which thrombin plays a role plays. These are particularly thromboembolic disorders such as Myocardial infarction, peripheral arterial occlusive disease, deep Venous thrombosis, pulmonary embolism and stroke. Furthermore they can help prevent reocclusion after opening arterial vessels used by mechanical methods or lysis become.
- the compounds according to the invention can be administered orally in the usual way or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally).
- parenterally subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally.
- the application can also be used with Vapors or sprays are done through the nasopharynx.
- the dosage depends on the age, condition and weight of the patient as well as on the type of application.
- the daily is Active ingredient dose per person between about 10 and 2000 mg oral administration and between approximately 1 and 200 mg with parenteral administration. This dose can be given in 2 to 4 single doses or once a day Depot form can be given.
- the new compounds can be used in the usual galenic Application forms can be used in solid or liquid form, e.g. as Tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These will made in the usual way.
- the active ingredients can the usual pharmaceutical auxiliaries such as tablet binders, fillers, Preservatives, tablet disintegrants, flow regulators, Plasticizers, wetting agents, dispersing agents, Emulsifiers, solvents, retardants, antioxidants and / or propellant gases are processed (see H. Sucker et al: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
- the application forms thus obtained contain the active ingredient usually in an amount of 0.1 to 99 percent by weight.
- the crude product was hydrogenated under a slight excess pressure of hydrogen in a mixture of 40 ml of methanol and 5 ml of glacial acetic acid with a spatula tip of 10% palladium on carbon at 50 ° C. After 5.5 h, the catalyst was filtered off, the solution was evaporated in vacuo and codistilled several times with methanol and toluene. After stirring the resulting product several times from DCM, 1.5 g (73% of theory over 3 steps) of clean N-hydroxysulfonyl-D-phenylalanyl-proline (p-amidinobenzyl) -amide were obtained, which according to NMR was present as betaine. Mp: 220-224 ° C, white powder, FAB-MS: 474 (MH) + .
- the core consists of 9 parts corn starch, 3 parts milk sugar and 1 part of Luviskol® VA 64 (vinylpyrrolidone-vinyl acetate copolymer 60: 40, cf. Pharm. Ind. 1962, 586).
- the saccharification mass consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts calcium carbonate and 1 part talc. The so produced Dragees are then given an enteric-coated tablet Provide cover.
- Example 1 100 g of the substance of Example 1 are placed in 5000 ml of water Addition of NaCl dissolved and adjusted to pH 6.0 with 0.1 N NaOH, so that a blood isotonic solution arises. 5 ml each Solution are filled into ampoules and sterilized.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4443390 | 1994-12-06 | ||
| DE4443390A DE4443390A1 (de) | 1994-12-06 | 1994-12-06 | Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten |
| PCT/EP1995/004646 WO1996017860A1 (de) | 1994-12-06 | 1995-11-25 | Neue dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0796271A1 EP0796271A1 (de) | 1997-09-24 |
| EP0796271B1 true EP0796271B1 (de) | 2000-02-02 |
Family
ID=6535046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP95941015A Expired - Lifetime EP0796271B1 (de) | 1994-12-06 | 1995-11-25 | Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5852051A (ja) |
| EP (1) | EP0796271B1 (ja) |
| JP (1) | JPH10509727A (ja) |
| CN (1) | CN1168673A (ja) |
| AT (1) | ATE189458T1 (ja) |
| AU (1) | AU699579B2 (ja) |
| BR (1) | BR9509970A (ja) |
| CA (1) | CA2207874A1 (ja) |
| CZ (1) | CZ153797A3 (ja) |
| DE (2) | DE4443390A1 (ja) |
| ES (1) | ES2143666T3 (ja) |
| FI (1) | FI972384A0 (ja) |
| HU (1) | HU222353B1 (ja) |
| IL (1) | IL116231A (ja) |
| MX (1) | MX9704050A (ja) |
| NO (1) | NO972559L (ja) |
| RU (1) | RU2152953C1 (ja) |
| TW (1) | TW336222B (ja) |
| WO (1) | WO1996017860A1 (ja) |
| ZA (1) | ZA9510295B (ja) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9900043D0 (sv) * | 1999-01-11 | 1999-01-11 | Astra Ab | New use |
| US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| SE9602263D0 (sv) | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
| US6200967B1 (en) | 1996-06-25 | 2001-03-13 | Eli Lilly And Company | Anticoagulant agents |
| US5863929A (en) * | 1996-06-25 | 1999-01-26 | Eli Lilly And Company | Anticoagulant agents |
| AR013084A1 (es) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados |
| SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
| WO2000061608A2 (de) * | 1999-04-09 | 2000-10-19 | Basf Aktiengesellschaft | Niedermolekulare inhibitoren von komplementproteasen |
| EP1182207B1 (en) * | 2000-08-11 | 2007-04-18 | Dendreon Corporation | Non-covalent inhibitors of urokinase and blood vessel formation |
| WO2002014349A2 (en) * | 2000-08-11 | 2002-02-21 | Corvas International, Inc. | Non-covalent inhibitors of urokinase and blood vessel formation |
| DE10049937A1 (de) * | 2000-10-06 | 2002-04-11 | Knoll Ag | Niedermolekulare Inhibitoren von Serinproteasen mit Polyhydroxyalkyl- und Polyhydroxycycloalkylresten |
| CH695999A5 (de) | 2002-02-28 | 2006-11-15 | Wilex Ag | Verfahren zur Herstellung von 3- Amidinophenylalanin-Derivaten. |
| DE102004029812A1 (de) * | 2004-06-19 | 2006-05-24 | Clariant Gmbh | Verfahren zur Herstellung von Nitrilen aus Aldehydoximen durch Umsetzung mit Alkylphosphonsäureanhydriden |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9103612D0 (sv) * | 1991-12-04 | 1991-12-04 | Astra Ab | New peptide derivatives |
| AU675981B2 (en) * | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
| SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| CA2140598C (en) * | 1994-01-27 | 2010-03-09 | Masahiro Ohshima | Prolineamide derivatives |
| ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
-
1994
- 1994-12-06 DE DE4443390A patent/DE4443390A1/de not_active Withdrawn
-
1995
- 1995-11-25 WO PCT/EP1995/004646 patent/WO1996017860A1/de not_active Application Discontinuation
- 1995-11-25 CZ CZ971537A patent/CZ153797A3/cs unknown
- 1995-11-25 JP JP8517287A patent/JPH10509727A/ja active Pending
- 1995-11-25 AU AU42559/96A patent/AU699579B2/en not_active Ceased
- 1995-11-25 CA CA002207874A patent/CA2207874A1/en not_active Abandoned
- 1995-11-25 RU RU97112398/04A patent/RU2152953C1/ru active
- 1995-11-25 AT AT95941015T patent/ATE189458T1/de not_active IP Right Cessation
- 1995-11-25 US US08/849,364 patent/US5852051A/en not_active Expired - Fee Related
- 1995-11-25 BR BR9509970A patent/BR9509970A/pt not_active Application Discontinuation
- 1995-11-25 HU HU9702107A patent/HU222353B1/hu not_active IP Right Cessation
- 1995-11-25 CN CN95196669A patent/CN1168673A/zh active Pending
- 1995-11-25 DE DE59507755T patent/DE59507755D1/de not_active Expired - Fee Related
- 1995-11-25 MX MX9704050A patent/MX9704050A/es not_active IP Right Cessation
- 1995-11-25 ES ES95941015T patent/ES2143666T3/es not_active Expired - Lifetime
- 1995-11-25 EP EP95941015A patent/EP0796271B1/de not_active Expired - Lifetime
- 1995-12-01 IL IL11623195A patent/IL116231A/xx not_active IP Right Cessation
- 1995-12-05 ZA ZA9510295A patent/ZA9510295B/xx unknown
- 1995-12-09 TW TW084113131A patent/TW336222B/zh active
-
1997
- 1997-06-05 FI FI972384A patent/FI972384A0/fi unknown
- 1997-06-05 NO NO972559A patent/NO972559L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO972559L (no) | 1997-08-05 |
| RU2152953C1 (ru) | 2000-07-20 |
| CZ153797A3 (cs) | 1998-02-18 |
| FI972384A (fi) | 1997-06-05 |
| IL116231A0 (en) | 1996-03-31 |
| AU4255996A (en) | 1996-06-26 |
| AU699579B2 (en) | 1998-12-10 |
| ZA9510295B (en) | 1997-06-05 |
| HUT77289A (hu) | 1998-03-30 |
| DE59507755D1 (de) | 2000-03-09 |
| DE4443390A1 (de) | 1996-06-13 |
| CN1168673A (zh) | 1997-12-24 |
| ES2143666T3 (es) | 2000-05-16 |
| IL116231A (en) | 2001-01-28 |
| NO972559D0 (no) | 1997-06-05 |
| TW336222B (en) | 1998-07-11 |
| MX9704050A (es) | 1997-08-30 |
| FI972384A0 (fi) | 1997-06-05 |
| HU222353B1 (hu) | 2003-06-28 |
| US5852051A (en) | 1998-12-22 |
| EP0796271A1 (de) | 1997-09-24 |
| ATE189458T1 (de) | 2000-02-15 |
| JPH10509727A (ja) | 1998-09-22 |
| CA2207874A1 (en) | 1996-06-13 |
| WO1996017860A1 (de) | 1996-06-13 |
| BR9509970A (pt) | 1997-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0796271B1 (de) | Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten | |
| DE69418083T2 (de) | Verbindungen mit eine Sulfonamid- und einer Amidinogruppe, ihr Herstellungsverfahren und sie enthaltende pharmazeutische Zubereitungen | |
| EP0236872B1 (de) | Hydroxylaminderivate, deren Herstellung und Verwendung für Heilmittel | |
| EP0871653B1 (de) | Neue aminosäurederivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende pharmazeutische zusammensetzungen | |
| DE60031577T2 (de) | Hemmer der zelladhäsion | |
| DE3689508T2 (de) | Peptide. | |
| EP0956294B1 (de) | Thrombininhibitoren | |
| WO1996025426A1 (de) | Neue dipeptidische amidine als thrombin-inhibitoren | |
| DE19510566A1 (de) | Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel | |
| WO1995035309A1 (de) | Neue thrombininhibitoren, ihre herstellung und verwendung | |
| WO1996024609A1 (de) | Thrombininhibitoren | |
| EP1294742B1 (de) | Urokinase-hemmstoffe | |
| DE3508251A1 (de) | Dipeptide | |
| WO1992016549A1 (de) | Para-substituierte phenylalanin-derivate | |
| DD236522A5 (de) | Verfahren zur herstellung medizinisch wertvoller verbindungen und zwischenverbindungen | |
| EP0991626A2 (de) | Pyrimidin-2,4,6-trion-derivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel | |
| DE69431359T2 (de) | Prolyl-endopeptidaseinhibitoren | |
| DE4121947A1 (de) | 2-(3-(4-amidino-phenyl))-propionsaeurederivate, ihre herstellung und verwendung | |
| WO1999037668A1 (de) | Thrombininhibitoren | |
| EP1049673A1 (de) | Heterocyclische amidine als kallikrein protease inhibitoren | |
| WO2003076457A1 (de) | HEMMSTOFFE DES GERINNUNGSFAKTORS Xa, IHRE HERSTELLUNG UND VERWENDUNG | |
| DE4026614A1 (de) | Phosphonopyrrolidin- und piperidin-haltige pseudopeptide vom statintyp, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel gegen retroviren | |
| DE3325850A1 (de) | Substituierte peptide | |
| EP1169318A1 (de) | Prodrugs von thrombininhibitoren | |
| DE19504504A1 (de) | Heterocyclische Thrombininhibitoren |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19970520 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE ES FR GB IT LI NL SE |
|
| 17Q | First examination report despatched |
Effective date: 19971117 |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
| GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE ES FR GB IT LI NL SE |
|
| REF | Corresponds to: |
Ref document number: 189458 Country of ref document: AT Date of ref document: 20000215 Kind code of ref document: T |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
| REF | Corresponds to: |
Ref document number: 59507755 Country of ref document: DE Date of ref document: 20000309 |
|
| ITF | It: translation for a ep patent filed | ||
| GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) |
Effective date: 20000321 |
|
| ET | Fr: translation filed | ||
| REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2143666 Country of ref document: ES Kind code of ref document: T3 |
|
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
| 26N | No opposition filed | ||
| REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20030220 Year of fee payment: 8 Ref country code: ES Payment date: 20030220 Year of fee payment: 8 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: ABBOTT GMBH & CO. KG Free format text: BASF AKTIENGESELLSCHAFT##67056 LUDWIGSHAFEN (DE) -TRANSFER TO- ABBOTT GMBH & CO. KG#MAX-PLANCK-RING 2#65205 WIESBADEN (DE) Ref country code: CH Ref legal event code: NV Representative=s name: SCHMAUDER & PARTNER AG PATENTANWALTSBUERO |
|
| REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20030417 Year of fee payment: 8 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20030422 Year of fee payment: 8 Ref country code: AT Payment date: 20030422 Year of fee payment: 8 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20030425 Year of fee payment: 8 |
|
| NLS | Nl: assignments of ep-patents |
Owner name: ABBOTT GMBH & CO. KG |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20030502 Year of fee payment: 8 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20030530 Year of fee payment: 8 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20030617 Year of fee payment: 8 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031125 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031125 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031126 Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031126 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031130 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031130 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20031130 |
|
| BERE | Be: lapsed |
Owner name: *ABBOTT G.M.B.H. & CO. K.G. Effective date: 20031130 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040601 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040602 |
|
| EUG | Se: european patent has lapsed | ||
| GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20031125 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20040730 |
|
| NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20040601 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
| REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20031126 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED. Effective date: 20051125 |